The proposed Program represents a multi-disciplinary effort to study the pathogenesis of animal arterio- and atherosclerosis, and to obtain clues as to how to moderate or inhibit the process. Project I deals with the animal model, in which de-endothelialized rat or rabbit aortas are studied for their proliferative response. Platelet turnover will be correlated with it, the role of macrophages will be studied, and the sources of mitogenic factors will be explored. Cholesterol synthesis in the proliferating cells will be related to the development of lipid-containing lesions. Project 2 explores the effects of steriod hormones upon medial smooth muscle cells in tissue culture. It attempts to find, by structural chemical modifications, a hormone without extraneous side effects on other tissues. Project 3 is designed to evaluate vascular cell proliferative activity in relationship to the synthesized surface proteases and their inhibitors; and Project 4 explores the relationship between contractile proteins of endothelial cells and extracellular connective tissues, whereby changes in disease lead to de-endothelialization. Project 5 seeks to define the proteoglycan patterns of normal vessels and those that have been de-endothelialized. Its objective is to determine patterns in the development of vessel healing which will account for lesion passivation and the development of atherosclerotic changes. It is planned for all models to supply data to the others, so that biochemical, tissue culture, and in vivo results generate an integrated and comprehensive picture of induced animal disease that may be applicable to human pathology.